CN1694711A - A method of extending the dose range of vitamin d compounds - Google Patents

A method of extending the dose range of vitamin d compounds Download PDF

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CN1694711A
CN1694711A CNA038248883A CN03824888A CN1694711A CN 1694711 A CN1694711 A CN 1694711A CN A038248883 A CNA038248883 A CN A038248883A CN 03824888 A CN03824888 A CN 03824888A CN 1694711 A CN1694711 A CN 1694711A
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vitamin
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赫克托·F.·德卢卡
J.·韦斯利·派克
洛里·A.·普拉姆
尼鲁帕玛·K.·舍弗德
玛格丽特·克拉格特－达姆
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Abstract

Inhibitors of bone calcium resorption are administered to allow high doses of vitamine D compounds or mimetics to be given the intent of treating non-calcium related diseases such as cancer, psoriasis, and autoimmune disease without the dangers of calcification of kidney, heart, and aorta. Inhibitors of bone calcium resorption include the bis-phosphonates, OPG or the soluble RANKL receptor known as sRANK, and function to block the availabilite of calcium from bone thereby preventing hypercalcemia and the resulting calcification of soft tissues. Thus, high doses of 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3), its analogs, prodrugs, or mimetics can be utilized with minimal risk to a patient. Specifically, alendronate is shown to block the bone calcium mobilization activity of both 1,25-(OH)2D3 and its very potent analog, 2-methylene-19-nor(20S)-1alpha,25 dihydroxyvitamin D3.

Description

Enlarge the method for vitamin agent weight range
Background of invention
Poisoning by vitamin D is just known since vitamin D in 1992 is found.In fatsoluble vitamin, the vitamin A and the D that surpass physiological dose can cause poisoning.With regard to vitamin D, its toxicity is the result that blood calcium and serium inorganic phosphorus level raise, and blood calcium and serium inorganic phosphorus level raise and cause being mainly the calcification of kidney, heart, aorta and other tissue.Renal failure or can cause death as the depletion of heart and aortal other vitals.Also known, vitamin D must be through internal metabolism before realizing its function, and metabolism is a 25-hydroxy-vitamin D in liver earlier 3(25-OH-D 3) and afterwards in kidney metabolism be 1, the 25-dihydroxyvitamin D 3-(1,25-(OH) 2D 3).Then, 1,25-(OH) 2D 3Stimulate the absorption of intestinal calcium and phosphorus, the heavily absorption of increase kidney calcium, and the most important thing is, rely on process (the parathyroidhormone dependent process) mobilization of moderate stimulation calcium in bone at parathyroid hormone.Therefore, a kind of important and inevitable activity of natural complex D hormone is from bone mobilization calcium and the phosphorus directly related with dosage up to now.
Also known 1,25-(OH) 2D 3Act on the target gene response element by receptor RXR, thereby or stimulate or suppress and transcribe with the protein dimerization.Gene outcome realizes owing to 1,25-(OH) 2D 3Function.Development along with the mice of rejecting receptor, and II type VDDR is this discovery that is caused by vitamin D receptor (VDR) sudden change or various mutations, clearly, even the activity of vitamin D is not all to have major part to mediate by VDR yet.This receptor finds at some tissues that these tissues before never were considered to the target tissue of vitamin D effect and were considered in the nature of things do not work in the function of its mobilization calcium and phosphorus.These target tissues are the keratinocyte of parathyroid gland, skin, the island cell and the lymphocyte of pancreas.In addition, Suda and its colleague conclusively show, and the vitamin D hormone is as 1,25-(OH) 2D 3Cause promyelocyte to be divided into mononuclear cell, this is a kind of being considered to and the irrelevant effect of calcium.Because the inhibition of cancerous tissue growth in this differentiation and the culture, the probability that vitamin D compounds can be used to the cancer differentiation therapy presents excitingly.And, also known 1,25-(OH) 2D 3And many analog suppress autoimmune disease.With vitamin D compounds as 1,25-(OH) 2D 3And the application of some kinds of its analog topical therapeutic psoriasis diseases is another facts of fully determining.Yet, realize that by delivery of vitamin D compounds the primary effect that mainly is limited as vitamin D compounds of these Therapeutic Method normally is that cost improves plasma calcium and phosphorus with the sclerotin.Therefore, if the vitamin D compounds of administration too high dose, poisoning by vitamin D probably then.Once attempted synthetic can not raise blood calcium and can be still can be at interaction in vitro suppressing the novel vitamin D analogues of the cancerous cell in the culture, but many up to now these analog all be owing to they by tachymetabolism and cause inactivation to be non-high calcium courage and uprightness (non-calcemic).Though should research still continue, the invention provides a kind of alternative approach, but the vitamin D compounds of the relative high dose of administration, its analog or vitamin D analogies (mimetics) and the poisoning by vitamin D that do not occur together thus.Therefore, the medicine by administering drug combinations blocking-up bone calcium mobilization can suppress or prevent or minimize the mobilization of calcium in bone at least, thereby allow to be used for treatment of diseases with the vitamin D compounds or the analogies of more and more higher dosage when not needing increasing blood calcium.The invention provides this method.
Summary of the invention
The present invention uses the inhibitors of bone resorption of diphosphonate or calcitonin or the mediation of other osteoclast with blocking-up bone calcium mobilization, thereby and prevents that vitamin D compounds or vitamin D analoglike thing from causing hypercalcemia.As a result, can be to patient's administration high dose vitamin D compounds and the poisoning by vitamin D that only tool is very little or the danger of hypercalcemia, and it is remarkable to suppress the probability of cancer, psoriasis or autoimmune disease.More specifically, the invention provides and a kind ofly take high dose vitamin D compounds or vitamin D analogies and do not produce hypercalcemia or cause the method for poisoning by vitamin D, it comprises with suitable dosage to the bone calcium cell reabsorption inhibitor with the mammal effective dosage of vitamin D compounds or the treatment of vitamin D analogies.The present invention also provides treatment psoriasic method, and it comprises with vitamin D compounds or the vitamin D analogies of suitable dosage to the bone calcium cell reabsorption inhibitor of suffering from psoriasic patient's effective dosage and effective dose.In addition, treating the method for cancer that is selected from leukemia, colon cancer, breast carcinoma or the carcinoma of prostate comprises with suitable dosage to the bone calcium cell reabsorption inhibitor of patient's effective dosage of suffering from above-mentioned cancer and the vitamin D compounds or the vitamin D analogies of effective dose.Another aspect of the present invention is for treating the method that is selected from the autoimmune disease among multiple sclerosis, lupus (lupis), inflammatory bowel disease, type i diabetes, host-versus-graft reaction and the organ-graft refection, and it comprises with suitable dosage to the bone calcium cell reabsorption inhibitor of patient's administration effective dose of suffering from above-mentioned disease and the vitamin D compounds or the vitamin D analogies of effective dose.
1,25-(OH) 2D 3Cause the discovery of promyelocyte differentiation and the growth of inhibition promyelocyte to guide some researcheres to study the purposes of this differentiation, and the discovery that has caused vitamin D hormone and other medicine can induce osteoclast to form.The vitamin D hormone appears not only to participate in monocytic differentiation but also further participates in coenocytic formation and apocyte is transformed into the activation of active osteoclast.This is receptor-mediated by the generation of vitamin D hormone by its stimulating protein RANKL, and this protein RANKL and osteoclast precursor are combined into the RANKL receptor that is known as RANK, and this receptor is positioned at the film surface of osteoclast precursor and mature osteoclast.Activate the growth of osteoclast and the function of osteoclast just after this signal.(version) RANK of a kind of natural excretory solubility version is known as and protects ossein (OPG), its can by combine with film or the excretory RANKL of film in conjunction with to block this differentiation or activated pathway (reference example is as WO96/26271 PCT application).The synthetic recombinant soluble albumen that preliminary study has shown OPG or only contained RANK (sRANK) extracellular domain can prevent 1,25-(OH) 2D 3Inductive serum calcium increases.
Particularly, the present invention uses bone calcium mobilization inhibitor, particularly the synthetic RANK of diphosphonate, OPG, solubility comprise the OPG that is blended in people Fc or the long-lived chimeric protein of solubility RANK (OPG-Fc, sRANK-Fc) with the mobilization of blocking-up bone calcium, prevent hypercalcemia and the soft tissue calcification that is caused thus.Therefore, can be to 1 α of patient's high doses applied, 25-dihydroxyvitamin D 3(1,25-(OH) 2D 3), its analog, prodrug or other vitamin compound (this paper is called " analogies ") and the danger that only has very little generation hypercalcemia.Particularly, find that Alendronic Acid salt can block 1,25-(OH) 2D 3Analog 2-methylene-19-very effective with it be nor--(20S)-1 α, and the 25-dihydroxyvitamin D 3(this paper is called 2MD) both bone calcium mobilization activity.
The preferable methods according to the present invention, the patient at first takes bone calcium cell reabsorption inhibitor, and as diphosphonate, calcitonin, OPG, perhaps sRANK or other similar RANKL bonding agent or inhibitor (OPG-Fc, RANK-Fc) are to prevent the bone calcium mobilization.Can than before think may not can cause the higher dosage of hypercalcemia take novel vitamin D analogues or chemical compound thereafter.Perhaps, can take inhibitors of bone resorption and vitamin D compounds simultaneously.Therefore, when administration bone calcium mobilization blocking medicine, with regard to 1,25-(OH) 2D 3, its therapeutic dose can be extended to for 5 or 10 μ g/ patient/days from 0.5 μ g/ patient/day.This method can prevent the generation of hypercalcemia and cause obtaining can suppressing cancer, prevent autoimmune disease or alleviating psoriasic concentration.
Expect that the application of this method can allow the increase of dosage level more than 10 times of vitamin D compounds, and that the patient produces the danger of hypercalcemia is very low.
Description of drawings
These accompanying drawings are described the realization best mode of the present invention of imagination at present.
Fig. 1 gives behind the dosage body weight to the mapping of time for the mice with the inventive method treatment; And
Fig. 2 gives behind the dosage serum calcium to the block diagram of time for the mice with the inventive method treatment.
The specific embodiment
As used in description and claims; term " hydroxy-protective group " expression any group that is generally used for the temporary protection hydroxy functional group, for example alkoxy carbonyl, acyl group, alkyl silicyl or alkylaryl silicyl (hereinafter referred is " silicyl ") and alkoxyalkyl.Preferred those hydroxy-protective groups stable to alkali but that can remove easily when needed.The alkoxy carbonyl blocking group is that alkyl-O-CO-base is as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, benzyloxy carbonyl or allyloxy carbonyl.The alkanoyl that term " acyl group " expression has all isomeric form of 1 to 6 carbon atom; perhaps as the carboxyl alkanoyl with 1 to 6 carbon atom of oxalyl group, malonyl, succinyl group, glutaryl, the perhaps aryl-acyl of the benzoyl that replaces as benzoyl or halogen, nitro or alkyl.The straight or branched alkyl that " alkyl " representative of using in this description or claims has all isomeric form of 1 to 10 carbon atom.The alkoxyalkyl blocking group is the group as methoxy, ethoxyl methyl, methoxy ethoxy methyl or tetrahydrofuran base and THP trtrahydropyranyl.Preferred silicyl blocking group is trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethyl silicyl, diphenyl methyl silicyl, phenyl dimetylsilyl, diphenyl tert-butyl group silicyl and similar alkylating silicyl.Term " aryl " refers to phenyl, perhaps the phenyl that is replaced by alkyl, nitro or halogen.
" protected hydroxyl " for by any above-mentioned group that is generally used for temporarily or forever protecting hydroxy functional group, the hydroxyl of deriving or protecting as the defined silicyl in front, alkoxyalkyl, acyl group or alkoxy carbonyl.Term " hydroxy alkyl ", " deuterium substituted alkyl " reach " fluoroalkyl " and refer to respectively by the alkyl of one or more hydroxyls, deuterium or fluorine replacement.
Refer to serum calcium cancentration in this used term " hypercalcemia " and " poisoning by vitamin D " and be equal to or higher than 2mg/100ml serum." toxic dose " of vitamin D compounds for to as cause the dosage of hypercalcemia or poisoning by vitamin D during human mammal delivery of vitamin D compounds.
Term " suitable dosage " refers to suitable dosage and reasonable time at interval to patient's delivery of vitamin D compounds and bone calcium cell reabsorption inhibitor with therapeutic goal treatment of diseases scheme effectively.As well-known in field of pharmacology, above-mentioned dosage and interval can be adjusted according to disease, its order of severity of treatment and the reaction of receiving treatment.
Vitamin D compounds
Term " vitamin D compounds " comprises and activatedly can control in the various vitamin D courses of reaction in the mammal (vitamin D-responsive processes) one or more by VDR as used herein, promptly intestinal calcium absorption, bone mobilize, the chemical compound of bone mineralising and cell differentiation.Therefore, the vitamin D compounds that the present invention comprises comprises cholecalciferol and ergocalciferol and their metabolite, and the synthetic cholecalciferol and the ergocalciferol analog that show high calcium courage and uprightness or cell differentiation activity.This term " vitamin D compounds " also comprises the vitamin d compounds that does not have contact on the structure, is called " vitamin D analogies " herein, and it activates by VDR equally.And the vitamin D compounds that comprises of unrestricted the present invention, these synthetic cholecalciferols and ergocalciferol analog comprise this compounds, as 5,6-is trans-cholecalciferol and 5, and 6-is trans-ergocalciferol, fluorizated cholecalciferol, the cholecalciferol of side chain homologization and the Δ of side chain homologization 22Cholecalciferol and ergocalciferol that-cholecalciferol, the intercepted cholecalciferol of side chain, the nor-cholecalciferol of 19-and ergocalciferol and 2-position replace.
With regard to structure, the vitamin D compounds that the present invention comprised can be represented with following formula I:
R wherein 6And R 7Represent hydrogen or R respectively 6And R 7A common methylene, the R of representing 8Represent hydrogen, hydroxyl or hydroxyl and protected, R 9And R 10Can distinguish and represent hydrogen, alkyl, hydroxy alkyl or fluoro-alkyl, perhaps R independently 9And R 10Can represent together x wherein for from 2 to 5 integer-(CH 2) x-group, group-OY or=R 11R 12, R wherein 11And R 12Can be identical or different, be selected from hydrogen, alkyl, hydroxy alkyl and fluoro-alkyl respectively, perhaps R 11And R 12Represent together x wherein for from 2 to 5 integer-(CH 2) X-group, and the side-chain radical R of structure as implied above can represent the side chain type of any steroid.
More specifically; R can represent the alkyl of saturated or undersaturated 1 to 35 carbon atom, and it can be straight chain, side chain or ring-type and can contain one or more extra as hydroxyl or hydroxyl and protected, fluorine, carbonyl, ester group, epoxy radicals, amino or other heteroatomic substituent group.Following structure is represented the preferred side chain of this type,
Wherein spatial chemistry center (corresponding to the C-20 of steroid numbering) can have R or S configuration (being the native configurations or the 20-table configuration of carbon 20), and Z be selected from Y ,-OY ,-CH 2OY ,-C ≡ CY and-CH=CHY, wherein two keys can have cis or trans geometric isomer, and wherein Y be selected from hydrogen, methyl ,-COR 5The group following with structure:
Wherein m and n represent 0 to 5 integer, wherein R independently 1Be selected from hydrogen, deuterium, hydroxyl, hydroxyl and protected, fluorine, trifluoromethyl and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, wherein R 2, R 3And R 4Be independently selected from deuterium, deuterium substituted alkyl, hydrogen, fluorine, trifluoromethyl respectively and can be straight or branched and can randomly have hydroxyl or hydroxyl and protected substituent group C 1-5Alkyl, and R wherein 1With R 2Common represent carbonyl or alkylidene ,=CR 2R 3, or wherein p be from 2 to 5 integers-(CH 2) p-group, wherein R 3With R 4Common represent carbonyl or wherein q be from 2 to 5 integers-(CH 2) q-group, wherein R 5Represent hydrogen, hydroxyl, hydroxyl and protected or C 1-5Alkyl, and wherein any CH group that is positioned at 20,22 or 23 of side chains can replace by nitrogen-atoms, perhaps wherein any be positioned at 20,22 and 23-CH (CH 3) ,-(CH 2) m,-(CR 1R 2)-or-(CH 2) n-can be replaced by oxygen or sulphur atom respectively.
The wave-like line of C-20 place methyl substituents represents that carbon 20 can have R or S configuration.
The example of the particular importance of side chain is represented by formula (a) and (b), (c), (d) and structure (e)
Some instantiations that can be used for vitamin D compounds herein comprise vitamin D metabolism thing or analog, as vitamin D 3, vitamin D 2, 1 alpha-hydroxy vitamin D 3, 1 alpha-hydroxy vitamin D 2, 1 α, the 25-dihydroxyvitamin D 3, 1 α, the 25-dihydroxyvitamin D 2, 25-hydroxy-vitamin D 3, 25-hydroxy-vitamin D 2, 24,24-two fluoro-25-hydroxy-vitamin Ds 3, 24,24-two fluoro-1 α, 25-dihydroxyvitamin D 3, 24-fluoro-25-hydroxy-vitamin D 3, 24-fluoro-1 α, the 25-dihydroxyvitamin D 3, 2 β-fluoro-25-hydroxy-vitamin D 3, 2 β-fluoro-1 alpha-hydroxy vitamin D 3, 2 β-fluoro-1 α, the 25-dihydroxyvitamin D 3, 26,26,26,27,27,27-hexafluoro-25-hydroxy-vitamin D 3, 26,26,26,27,27,27-hexafluoro-1 α, 25-dihydroxyvitamin D 3, 24, the 25-dihydroxyvitamin D 3, 1 α, 24,25-trihydroxy vitamin D 3, 25, the 26-dihydroxyvitamin D 3, 1 α, 25,26-trihydroxy vitamin D 3, 23, the 25-dihydroxyvitamin D 3, 23,25,26-trihydroxy vitamin D 3, and corresponding 1 α hydroxylating form, 25-hydroxy-vitamin D 3-26,23-lactone and 1 α hydroxylation derivative thereof, hydroxy-vitamine D 3And 1 α, the 25-dihydroxyvitamin D 3Side chain demethyl, dinor-, three demethyls and four demethyl analog, 1 Alpha-hydroxy pregnacalciferol with and high and two high derivants, 1 α, 25-dihydroxy-24-table-vitamin D 2, 24-height-1, the 25-dihydroxyvitamin D 3, 24-is two high by-1, the 25-dihydroxyvitamin D 3, 24-three-hypers-1,25-trihydroxy vitamin D 3And 1 α, the 25-dihydroxyvitamin D 3Corresponding 26-or 26, the corresponding 19-demethyl of the chemical compound of the height of 27-position, two high or three-hypers analog and those acts as listed above and the chemical compound that 2-replaces.
It should be noted that in this description term " 24-height " refers to 24 of side chain carbon increases a methylene and term " 24-is two high " refers to 24 of side chain carbon and increases by two methylene.Similarly, term " three-hypers " refers to increases by three methylene.And, term " 26, the 27-dimethyl " thus refer to carbon 26 and 27 and increase R among the methyl formula I 3With R 4Example all be ethyl.Similarly, term " 26, the 27-diethyl " refers at carbon 26, thereby 27 increase R among the ethyl formula I 3With R 4Example all be propyl group.
When side chain was unsaturated, the concrete and preferred examples of the vitamin D compounds of structure I was:
1 alpha-hydroxy-2 2-dehydrogenation vitamin D 3
1 α, 25-dihydroxy-22-dehydrogenation vitamin D 3
25-hydroxyl-22-dehydrogenation vitamin D 3
24-height-1,25-dihydroxy-22-dehydrogenation vitamin D 3
24-is two high by-1,25-dihydroxy-22-dehydrogenation vitamin D 3
24-three-hypers-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-dimethyl-24-height-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-dimethyl-24-is two high by-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-dimethyl-24-three-hypers-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-diethyl-24-height-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-diethyl-24-is two high by-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-diethyl-24-three-hypers-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-dipropyl-24-height-1,25-dihydroxy-22-dehydrogenation vitamin D 3
26,27-dipropyl-24-is two high by-1,25-dihydroxy-22-dehydrogenation vitamin D 3And
26,27-dipropyl-24-three-hypers-1,25-dihydroxy-22-dehydrogenation vitamin D 3
When side chain was saturated, the concrete and preferred examples of the vitamin D compounds of structure I was:
1 alpha-hydroxy vitamin D 3
1 α, the 25-dihydroxyvitamin D 3
25-hydroxy-vitamin D 3
24-height-1, the 25-dihydroxyvitamin D 3
24-is two high by-1, the 25-dihydroxyvitamin D 3
24-three-hypers-1, the 25-dihydroxyvitamin D 3
26,27-dimethyl-24-height-1,25-dihydroxyvitamin D 3
26,27-dimethyl-24-is two high by-1, the 25-dihydroxyvitamin D 3
26,27-dimethyl-24-three-hypers-1,25-dihydroxyvitamin D 3
26,27-diethyl-24-height-1,25-dihydroxyvitamin D 3
26,27-diethyl-24-is two high by-1, the 25-dihydroxyvitamin D 3
26,27-diethyl-24-three-hypers-1,25-dihydroxyvitamin D 3
26,27-dipropyl-24-height-1,25-dihydroxyvitamin D 3
26,27-dipropyl-24-is two high by-1, the 25-dihydroxyvitamin D 3And
26,27-dipropyl-24-three-hypers-1,25-dihydroxyvitamin D 3
In the above listed vitamin D compounds,, then it should be added in the name if a specified substituent is connected in 2 in carbon.For example, if 2 in carbon connects an alkyl substituent and this alkyl substituent is a methyl, then title " 2-methyl " should be placed on each and names before the chemical compound.If ethyl is this alkyl substituent, then title " 2-ethyl " should be placed on each and names before the chemical compound, and the rest may be inferred.Equally, if carbon 2 places connect an alkylidene substituent group and this alkylidene substituent group is a methylene, then title " 2-methylene " should be placed on each and names before the chemical compound.If ethylidene is this alkylidene substituent group, then title " 2-ethylidene " should be placed on each and names before the chemical compound, and the rest may be inferred.2-alkyl-19-nor-vitamin D compounds has more complete description the 6th, 127 in No. 559 United States Patent (USP)s, and its disclosure is specially and in herein as a reference.2-alkylidene-19-nor-vitamin D compounds has more complete description the 5th, 843 in No. 928 United States Patent (USP)s, and its disclosure is specially and in herein as a reference.Other vitamin D compounds is disclosed in the 6th, 369, and in No. 099 United States Patent (USP), its disclosure is specially and in herein as a reference.In addition, be phenotype or non-natural configuration if be connected in the methyl of 20 in carbon, term " 20 (S) " or " 20-table " should be incorporated into each and name in the chemical compound.If need, the chemical compound of naming also can be has the above-mentioned formula (c) or (d) vitamin D of side chain 2Type and the 19-demethyl type that is connected in the positive methylene of 10 in A-ring carbon with two hydrogen atoms replacements.The 19-nor-vitamin D compounds has more complete description the 5th, 587 in No. 497 United States Patent (USP)s, and its disclosure is expressly and in herein as a reference.
The preferred vitamin D chemical compound that is applied in the inventive method is 1 α, the 25-dihydroxyvitamin D 3And 2-methylene-19-nor-20 (S)-1 α, the 25-dihydroxyvitamin D 3(this paper is called " 2MD ")
Preparation with vitamin D compounds of base structure I can be implemented by general method in common, and promptly bicyclic Windaus-Grundmann type ketone and the condensation of allyl type phosphine oxide are if the words that need are gone protection to C-1 and C-3 position at the back chemical compound then.Should be synthetic well-known, can be with reference to the 5th, 843,928 and 5,945, No. 410 United States Patent (USP)s are to obtain this technology more detailed description.
With regard to structure, the vitamin D analogies can by but be not limited to (Chem.Biol.6:265-275 such as Boehm, 1999) and (The Prostate 49:224-233 such as Polek, 2001) non-disconnected steroidal class (non-secosteroidal) the VDR part or derivatives thereof representative of report, its all open all specially and in herein as a reference.The example that activates the vitamin D analogies of VDR is those (Chem.Biol.6:265-275,1999) and bile acid lithocholic acid and some kinds of its derivants (Makishima etc., Science 296:1313-1316,2002) by evaluations such as Boehm.
Vitamin D analogies embodiment includes but not limited to following five kinds of chemical compounds:
Inhibitors of bone resorption
As mentioned before, the hypercalcemia of administration bone calcium cell reabsorption inhibitor to prevent to cause by vitamin D compounds.Term " the re-absorbed inhibitor of bone calcium " or " bone calcium cell reabsorption inhibitor " comprise blocking-up or block body heavily absorbs the ability of calcium in bone chemical compound at least substantially.This chemical compound comprises:
Estrogen,
Androgen,
As the re-absorbed cytokine of inhibition bone of interleukin (IL)-4, IL-12, IL-13, IL-18,
The activator of peroxisome hypertrophy activated form receptor (PPAR) γ of thiazolidinedione type (for example rosiglitazone (rosglitazone), pioglitazone (piaglitazone)) (Bendixen etc., Proc.Natl.Acad.Sci.USA 98:2443-2448,2001)
Calcitonin,
Diphosphonate (for example Allan phosphate, Risedronate),
The receptor activators (Childs etc., J.Bone Miner.Res.17:192-199,2002) of NFkB (RANK) extracellular domain preparation,
The RANK analogies,
Solubility RANK-chimeric protein (RANK-Fc) (Childs etc., J.Bone Miner.Res.17:192-199,2002),
Protect ossein (OPG) (Morony etc., J.Bone Miner.Res.14:1478-1485,1999),
OPG chimeric protein (OPG-Fc) (Morony etc., J.Bone Miner.Res.14:1478-1485,1999),
OPG analogies (Takasaki etc., Nature Biotech 15:1266-1270,1997),
TNF receptor associated factor 6 (Traf6) is inveigled peptide (Lomaga etc., Gene﹠amp; Develop.13:1015-1024,1999; Ye etc., Nature 418:443-447,2002),
Chimeric permeable membrane Traf6 inveigles peptide (Ye etc., Nature 418:443-447,2002),
Traf6 inveigles peptide mimics,
Src inhibitor (Wong etc., Mol.Cell 4:1041-1049,1999),
The outer receptor kinase (ERKs) of born of the same parents, the terminal kinases (JNKs) of c-Jun N-, stress activated protein kinase (SAPKs) inhibitor (Darnay etc., J.Biol.Chem.274:7724-7731,1999 (p38s); Matsumoto etc., J.Biol.Chem.275:31155-31161,2000),
The micromolecular inhibitor of peptide/activator protein-I (AP-1),
The micromolecular inhibitor of peptide/c-Fos,
Micromolecular inhibitor (Franzoso etc., the Genes﹠amp of peptide/nuclear factor Kappa B (NFkB); Develop.11:3482-3496,1997),
The micromolecular inhibitor of peptide/inhibition type kinase (IK) β,
The micromolecular inhibitor of peptide/inhibition type kinase (IK α, IK β, IKKs),
Film is in conjunction with the micromolecule antagonist of RANK,
The micromolecular inhibitor of RANK part trimerization or activation,
The inhibitor that contains RGD (Nakamura etc., Endocrinology 139:5182-5193,1998) of the integrin that osteoclast is expressed,
The small molecule mimetics of integrin inhibitor (Nakamura etc., Endocrinology139:5182-5193,1998),
Cathespin K inhibitor,
Tartrate tolerance acid phosphoric acid enzyme inhibitor, and
Vacuolate atpase inhibitor.
Above-claimed cpd can be according to desired result and independent or is multiplely united use.
For therapeutic purposes, according to conventional method known in the art, vitamin D compounds by formula I definition, or as by (Chem.Biol.6:265-275 such as Boehm, 1999) and (The Prostate 49:224-233 such as Polek, 2001) Ding Yi vitamin D analogies and bone calcium cell reabsorption inhibitor can be prepared respectively and be used for materia medica application as described below, as as the solution in the harmless solvent, perhaps Emulsion, suspensoid or the dispersant in The suitable solvent or the carrier perhaps adopts pill, tablet or the capsule of solid carrier.Any this prescription also can comprise other medicines and learn acceptable and nontoxic excipient, as stabilizing agent, antioxidant, adhesive, coloring agent or emulsifying agent or correctives.
Vitamin D compounds or analogies and bone calcium cell reabsorption inhibitor can be oral respectively, local, parenteral route or transdermal administration.Vitamin D compounds or analogies and/or bone calcium cell reabsorption inhibitor are suitable for by injection or intravenous infusion or suitable sterile solution administration, or be form through the liquid or solid of esophagus administration, perhaps be cream, ointment, patch or the similarly carrier administration of suitable transdermal administration.Dosage be every day 0.1 μ g to every day 100 μ g vitamin D compounds and dosage be every day 7.0mg to every day 700mg bone calcium cell reabsorption inhibitor be applicable to therapeutic purposes.As known in the art, above-mentioned dosage can be according to the disease of being treated, its order of severity and reaction adjustment.Usually with the q.s administration, thereby can provide 0.1mg/kg bone calcium cell reabsorption inhibitor to the 10mg/kg body weight.Vitamin D compounds or analogies and/or bone calcium cell reabsorption inhibitor can be distinguished suitably independent separately administration, the administration simultaneously of dosage that perhaps can be suitable is perhaps in vitamin D compounds or analogies and/or the together administration of bone calcium cell reabsorption inhibitor finding to be suitable under the condition of different biological activity degree to change gradually with another kind of dosage.
The compositions that is applied to the treatment of the pernicious or autoimmune disease of above-mentioned psoriasis, cancer and other comprise the vitamin D compounds of one or more following formulas I definition of effective dose or analogies and one or more in the bone calcium cell reabsorption inhibitor of this definition as active component, and the pharmaceutical carrier that is fit to separately.Said composition can be basically administration simultaneously or preferable methods be the compositions elder generation administration that contains bone calcium cell reabsorption inhibitor, administration afterwards contains the compositions of vitamin D compounds.Also imagination contains the two single compositions of vitamin D compounds or analogies and bone calcium cell reabsorption inhibitor.The inhibitors of bone resorption that the effective dose that can be used for all this compositionss of the present invention is the about 0.1 μ g of every gram compositions to the vitamin D compounds of 100 μ g or analogies and every gram compositions 7mg to 700mg, and can prepare and be used for part, transdermal, oral or parenteral administration.
Said composition can be mixed with cream, lotion, ointment, topical patch, pill, capsule or tablet, the liquid form of solution, Emulsion, dispersant or suspensoid perhaps as at materia medica in harmless and acceptable solvent or the oil, and above-mentioned preparation can comprise other medicines in addition and learn harmless or useful composition, as stabilizing agent, antioxidant, emulsifying agent, coloring agent, adhesive or correctives.
Said composition is suitable for the q.s administration to produce a desired effect.Above-mentioned dosage is fit to, and it must be appreciated, as known in the art, the amount that is provided must be adjusted according to disease severity and patient's the state of an illness and reaction.
Dosage form of the present invention comprise active component with and the materia medica acceptable carrier that is suitable for and other optional therapeutic component.It is compatible and harmless to its excipient that this carrier is necessary for other composition that " acceptable " meaning in itself and the preparation.
The dosage form of the present invention that is fit to oral administration can take all to contain as each the form of discrete unit of capsule, sachet, tablet or the lozenge of the active component of scheduled volume; Powder or granule form; The solution in waterborne liquid or non-aqueous liquid or the form of suspensoid; The perhaps form of oil in water emulsion or water in oil emulsion.
The dosage form of rectally can take to comprise active component and form as the suppository of the substrate of cocoa butter, the perhaps form of enema.
The dosage form that is fit to parenteral administration generally includes the aseptic oiliness or the aqueous formulation of active component, and said preparation preferably oozes with receiver's blood etc.
The dosage form that is fit to topical comprises liquid or semi-liquid preparations, as liniment, lotion, applicator, as the oil-in-water or the water in oil Emulsion of cream, ointment or paste; Perhaps as the solution or the suspensoid of drop; Perhaps spray.
This dosage form can be represented by dosage unit form usually, and can be prepared by the well-known any method of pharmaceutical field.Term " dosage " unit " mean a unit, promptly can be used as physics and chemically stable unit dose single dosage to patient's administration, it comprises that active component itself or itself and solid or liquid medicine learn the mixture of diluent or carrier.
Embodiment
From Harlan-Sprague Dawley acquisition male CD1 mice in eight ages in week and (1970) described purification recipes 11 that contain 0.47% calcium, 0.3% phosphorus such as feeding such as Suda, and vitimin supplement A, D, E and K.Arrive two days later, make this Mus then eat to be all the recipe that recipe 11 but contains 0.02% calcium, 0.3% phosphorus and additional A, D, E and K.Thereby, the animal no calcium meals of taking food basically.Transfer the low calcium meal of feed two days later animal, give following dosage to it: 1 of the 2MD of 1.7 μ g/kg body weight and/or 4.5 μ g/kg body weight or 500 μ g/kg body weight, 25-(OH) 2D 3Earlier mice is divided into 6/ group and oral administration administration provide shown in the vitamin D compounds of dosage level.To be dissolved to available from the alendronate of Sigma in the phosphate-buffered salt and through the volume of intraperitoneal administration 100 μ l.The treatment back was collected serum on the the 2nd, 3,4 and 8 day.With Atomic Absorption Spectrometry total serum calcium.
The body weight of periodic measurement animal during whole test.
The treatment group
N=6 animal/group
Group 1-Neobee oil (4mg/kg body weight)
Group 2-1X PBS (100 μ l)
Group 3-alendronate (～1.75mg/kg body weight)+Neobee oil
Group 4-2MD (4.5 μ g/kg body weight are in Neobee oil)+1X PBS
Group 5-2MD (4.5 μ g/kg body weight are in Neobee oil)+alendronate (～1.75mg/kg body weight)
Group 6-1,25-(OH) 2D 3(500 μ g/kg body weight are in Neobee oil)+1X PBS
Group 7-1,25-(OH) 2D 3(500 μ g/kg body weight are in Neobee oil)+alendronate (～1.75mg/kg body weight)
Group 8-alendronate (～1.75mg/kg is dissolved in PBS), 2MD behind the 24hr (4 μ g/kg body weight)
Oil and vitamin D compounds all pass through the oral gavage administration.Alendronate and PBS intraperitoneal administration 100 μ l volumes.
The result
As shown in table 1, body weight does not change except that the group of accepting 2MD.Therefore, the indication that loses weight of hypercalcemia and poisoning is very obvious in accepting the mice of 2MD.All other groups are kept its body weight at duration of test.Lower figure explanation, identical with 2MD, 1,25-(OH) 2D 3In 2 days, cause serum calcium significantly to raise.2MD shows further hypercalcemia effect after 3 days, and 1,25-(OH) 2D 3Effect disappear.To the 4th day, 1,25-(OH) 2D 3Do not show the hypercalcemia effect, and 2MD still shows the hypercalcemia value of 12.5mg/100ml.The administration alendronate obviously can be blocked by 1 25-(OH) 2D 3Or the serum calcium that causes of 2MD raises, and alendronate itself does not change serum calcium cancentration.These results prove, can thoroughly prevent with potent novel vitamin D analogues, 2MD or 1 25-(OH) by taking the diphosphonate alendronate simultaneously 2D 3Self treat back calcium and in bone, mobilize the hypercalcemia that causes.Thereby, may in the presence of alendronate, continue with high-caliber 2MD mice to be treated safely, and the effectiveness of other disease that therefore can be applicable to determine that its treatment malignant tumor or some calcium are not participated.According to expection, calcitonin can be used to similarly prevent with the sclerotin be cost rising blood calcium or be used to prevent bone source hypercalcemia with OPG, sRANK, OPG-Fc or RANK-Fc.

Claims (68)

1, a kind of to mammal administration toxic dose vitamin D compounds and do not produce the method for hypercalcemia, it comprises with the bone calcium cell reabsorption inhibitor of proper dosage scheme to described mammal effective dosage.
2, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor is an oral administration.
3, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor is non-gastrointestinal administration.
4, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor is a transdermal administration.
5, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor is a topical.
6, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor are the dosed administrations with 0.1mg/kg body weight-100mg/kg body weight.
7, the method for claim 1, the administration before vitamin D compounds of wherein said bone calcium cell reabsorption inhibitor.
8, the method for claim 1, the basic administration simultaneously of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds.
9, the method for claim 1, wherein said vitamin D compounds is selected from the chemical compound with following structure
R wherein 6And R 7Represent hydrogen or R respectively 6And R 7A common methylene, the R of representing 8Represent hydrogen, hydroxyl or hydroxyl and protected, R 9And R 10Can distinguish and represent hydrogen, alkyl, hydroxy alkyl or fluoro-alkyl, perhaps R independently 9And R 10Can represent together x wherein for from 2 to 5 integer-(CH 2) X-group, group-OY or=R 11R 12, R wherein 11And R 12Can be identical or different, be selected from hydrogen, alkyl, hydroxy alkyl and fluoro-alkyl respectively, perhaps R 11And R 12Represent together x wherein for from 2 to 5 integer-(CH 2) X-group, and radicals R can be represented by the following formula structure
Figure A038248880003C2
Wherein the spatial chemistry center of 20 in carbon can be R or S configuration, and Z be selected from Y ,-OY ,-CH 2OY ,-C ≡ CY and-CH=CHY, wherein two keys can have cis or trans geometric isomer, and wherein Y be selected from hydrogen, methyl ,-COR 5The group following with structure:
Figure A038248880003C3
Wherein m and n represent 0 to 5 integer, wherein R independently 1Be selected from hydrogen, deuterium, hydroxyl, hydroxyl and protected, fluorine, trifluoromethyl and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, wherein R 2, R 3And R 4Be independently selected from deuterium, deuterium substituted alkyl, hydrogen, fluorine, trifluoromethyl respectively and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, and R wherein 1With R 2Common represent carbonyl or alkylidene ,=CR 2R 3, or wherein p be from 2 to 5 integers-(CH 2) P-group, wherein R 3With R 4Common represent carbonyl or wherein q be from 2 to 5 integers-(CH 2) q-group, wherein R 5Represent hydrogen, hydroxyl, hydroxyl and protected or C 1-5Alkyl, and wherein any CH group that is positioned at 20,22 or 23 of side chains can replace by nitrogen-atoms, perhaps wherein any be positioned at 20,22 and 23-CH (CH 3) ,-(CH 2) m ,-(CR 1R 2)-or-(CH 2) n-can be replaced by oxygen or sulphur atom respectively.
10, the method for claim 1, wherein said vitamin D compounds are 2-methylene-19-nor-20 (S)-1 α, the 25-dihydroxyvitamin D 3
11, the method for claim 1, wherein said vitamin D compounds are 1 α, the 25-dihydroxyvitamin D 3
12, the method for claim 1, wherein said vitamin D compounds are to be selected from any vitamin D analogies that can combine and activate the chemical compound of its transcriptional capability with VDR.
13, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor is selected from following group:
Estrogen,
Androgen,
Suppress the re-absorbed cytokine of bone,
The activator of peroxisome hypertrophy activated form receptor (PPAR) γ of thiazolidinediones,
Calcitonin,
Diphosphonate,
The receptor activators of NFkB (RANK) extracellular domain preparation,
The RANK analogies,
Solubility RANK-chimeric protein (RANK-Fc),
Protect ossein (OPG),
OPG chimeric protein (OPG-Fc),
The OPG analogies,
TNF receptor associated factor 6 (Traf6) is inveigled peptide,
Chimeric permeable membrane Traf6 inveigles peptide,
Traf6 inveigles peptide mimics,
The src inhibitor,
The outer receptor kinase (ERKs) of born of the same parents, the terminal kinases (JNKs) of c-Jun N-or inhibitor that stress activated protein kinase (SAPKs),
The micromolecular inhibitor of peptide/activator protein-I (AP-1),
The micromolecular inhibitor of peptide/c-Fos,
The micromolecular inhibitor of peptide/nuclear factor Kappa B (NFkB),
The micromolecular inhibitor of peptide/inhibition type kinase (IK) β,
The micromolecular inhibitor of peptide/inhibition type kinase (IK α, IK β, IKKs),
Film is in conjunction with the micromolecule antagonist of RANK,
The micromolecular inhibitor of RANK part trimerization or activation,
The inhibitor that contains RGD of the integrin that osteoclast is expressed,
The small molecule mimetics of integrin inhibitor,
Cathespin K inhibitor,
Tartrate tolerance acid phosphoric acid enzyme inhibitor, and
Vacuolate atpase inhibitor.
14, the method for claim 1, wherein said bone calcium cell reabsorption inhibitor is an alendronate.
15, the method for claim 1, wherein said mammal are human.
16, the psoriasic method of a kind of treatment, it comprises with the proper dosage scheme to the bone calcium cell reabsorption inhibitor of suffering from psoriasic patient's effective dosage and the vitamin D compounds of effective dose.
17, method as claimed in claim 16, the administration before vitamin D compounds of wherein said bone calcium cell reabsorption inhibitor.
18, method as claimed in claim 16, the basic administration simultaneously of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or analogies.
19, method as claimed in claim 16, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are oral administrations.
20, method as claimed in claim 16, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are parenteral administrations.
21, method as claimed in claim 16, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are transdermal administrations.
22, method as claimed in claim 16, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are topicals.
23, method as claimed in claim 16, wherein said bone calcium cell reabsorption inhibitor are that described vitamin D compounds is the dosed administration with about 0.1 μ g/ days-100 μ g/ days with the dosed administration of about 7mg/ days-700mg/ days.
24, method as claimed in claim 16, wherein said vitamin D compounds is selected from the chemical compound with following structure
Figure A038248880007C1
R wherein 6And R 7Represent hydrogen or R respectively 6And R 7A common methylene, the R of representing 8Represent hydrogen, hydroxyl or hydroxyl and protected, R 9And R 10Can distinguish and represent hydrogen, alkyl, hydroxy alkyl or fluoro-alkyl, perhaps R independently 9And R 10Can represent together x wherein for from 2 to 5 integer-(CH 2) X-group, group-OY or=R 11R 12, R wherein 11And R 12Can be identical or different, be selected from hydrogen, alkyl, hydroxy alkyl and fluoro-alkyl respectively, perhaps R 11And R 12Represent together x wherein for from 2 to 5 integer-(CH 2) X-group, and radicals R can be represented by the following formula structure
Wherein the spatial chemistry center of 20 in carbon can be R or S configuration, and Z be selected from Y ,-OY ,-CH 2OY ,-C ≡ CY and-CH=CHY, wherein two keys can have cis or trans geometric isomer, and wherein Y be selected from hydrogen, methyl ,-COR 5The group following with structure:
Wherein m and n represent 0 to 5 integer, wherein R independently 1Be selected from hydrogen, deuterium, hydroxyl, hydroxyl and protected, fluorine, trifluoromethyl and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, wherein R 2, R 3And R 4Be independently selected from deuterium, deuterium substituted alkyl, hydrogen, fluorine, trifluoromethyl respectively and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, and R wherein 1With R 2Common represent carbonyl or alkylidene ,=CR 2R 3, or wherein p be from 2 to 5 integers-(CH 2) P-group, wherein R 3With R 4Common represent carbonyl or wherein q be from 2 to 5 integers-(CH 2) q-group, wherein R 5Represent hydrogen, hydroxyl, hydroxyl and protected or C 1-5Alkyl, and wherein any CH group that is positioned at 20,22 or 23 of side chains can replace by nitrogen-atoms, perhaps wherein any be positioned at 20,22 and 23-CH (CH 3) ,-(CH 2) m ,-(CR 1R 2)-or-(CH 2) n-can be replaced by oxygen or sulphur atom respectively.
25, method as claimed in claim 16, wherein said vitamin D compounds are 2-methylene-19-nor-20 (S)-1 α, the 25-dihydroxyvitamin D 3
26, method as claimed in claim 16, wherein said vitamin D compounds are 1 α, the 25-dihydroxyvitamin D 3
27, method as claimed in claim 16, wherein said vitamin D compounds are to be selected from any vitamin D analogies that can combine and activate the chemical compound of its transcriptional capability with VDR.
28, method as claimed in claim 16, wherein said bone calcium cell reabsorption inhibitor is selected from following group:
Estrogen,
Androgen,
Suppress the re-absorbed cytokine of bone,
The activator of peroxisome hypertrophy activated form receptor (PPAR) γ of thiazolidinediones,
Calcitonin,
Diphosphonate,
The receptor activators of NFkB (RANK) extracellular domain preparation,
The RANK analogies,
Solubility RANK-chimeric protein (RANK-Fc),
Protect ossein (OPG),
OPG chimeric protein (OPG-Fc),
The OPG analogies,
TNF receptor associated factor 6 (Traf6) is inveigled peptide,
Chimeric permeable membrane Traf6 inveigles peptide,
Traf6 inveigles peptide mimics,
The src inhibitor,
The outer receptor kinase (ERKs) of born of the same parents, the terminal kinases (JNKs) of c-Jun N-or inhibitor that stress activated protein kinase (SAPKs),
The micromolecular inhibitor of peptide/activator protein-I (AP-1),
The micromolecular inhibitor of peptide/c-Fos,
The micromolecular inhibitor of peptide/nuclear factor Kappa B (NFkB),
The micromolecular inhibitor of peptide/inhibition type kinase (IK) β,
The micromolecular inhibitor of peptide/inhibition type kinase (IK α, IK β, IKKs),
Film is in conjunction with the micromolecule antagonist of RANK,
The micromolecular inhibitor of RANK part trimerization or activation,
The inhibitor that contains RGD of the integrin that osteoclast is expressed,
The small molecule mimetics of integrin inhibitor,
Cathespin K inhibitor,
Tartrate tolerance acid phosphoric acid enzyme inhibitor, and
Vacuolate atpase inhibitor.
29, method as claimed in claim 16, wherein said bone calcium cell reabsorption inhibitor is an alendronate.
30, a kind of treatment is selected from the method for leukemia, colon cancer, breast carcinoma or carcinoma of prostate, and it comprises with the proper dosage scheme to the bone calcium cell reabsorption inhibitor of patient's effective dosage of suffering from above-mentioned disease and the vitamin D compounds of effective dose.
31, method as claimed in claim 30, the administration before vitamin D compounds of wherein said bone calcium cell reabsorption inhibitor.
32, method as claimed in claim 30, the basic administration simultaneously of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds.
33, method as claimed in claim 30, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are oral administrations.
34, method as claimed in claim 30, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are parenteral administrations.
35, method as claimed in claim 30, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are transdermal administrations.
36, method as claimed in claim 30, wherein said vitamin D compounds are the dosed administrations with about 0.1 μ g/ days-100 μ g/ days, and described bone calcium cell reabsorption inhibitor is the dosed administration with about 7mg/ days-700mg/ days.
37, method as claimed in claim 30, wherein said vitamin D compounds is selected from the chemical compound with following structure
R wherein 6And R 7Represent hydrogen or R respectively 6And R 7A common methylene, the R of representing 8Represent hydrogen, hydroxyl or hydroxyl and protected, R 9And R 10Can distinguish and represent hydrogen, alkyl, hydroxy alkyl or fluoro-alkyl, perhaps R independently 9And R 10Can represent together x wherein for from 2 to 5 integer-(CH 2) X-group, group-OY or=R 11R 12, R wherein 11And R 12Can be identical or different, be selected from hydrogen, alkyl, hydroxy alkyl and fluoro-alkyl respectively, perhaps R 11And R 12Represent together x wherein for from 2 to 5 integer-(CH 2) X-group, and radicals R can be represented by the following formula structure
Figure A038248880011C2
Wherein the spatial chemistry center of 20 in carbon can be R or S configuration, and Z be selected from Y ,-OY ,-CH 2OY ,-C ≡ CY and-CH=CHY, wherein two keys can have cis or trans geometric isomer, and wherein Y be selected from hydrogen, methyl ,-COR 5The group following with structure:
Figure A038248880011C3
Wherein m and n represent 0 to 5 integer, wherein R independently 1Be selected from hydrogen, deuterium, hydroxyl, hydroxyl and protected, fluorine, trifluoromethyl and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, wherein R 2, R 3And R 4Be independently selected from deuterium, deuterium substituted alkyl, hydrogen, fluorine, trifluoromethyl respectively and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, and R wherein 1With R 2Common represent carbonyl or alkylidene ,=CR 2R 3, or wherein p be from 2 to 5 integers-(CH 2) P-group, wherein R 3With R 4Common represent carbonyl or wherein q be from 2 to 5 integers-(CH 2) q-group, wherein R 5Represent hydrogen, hydroxyl, hydroxyl and protected or C 1-5Alkyl, and wherein any CH group that is positioned at 20,22 or 23 of side chains can replace by nitrogen-atoms, perhaps wherein any be positioned at 20,22 and 23-CH (CH 3) ,-(CH 2) m,-(CR 1R 2)-or-(CH 2) n-can be replaced by oxygen or sulphur atom respectively.
38, method as claimed in claim 30, wherein said vitamin D compounds are 2-methylene-19-nor-20 (S)-1 α, the 25-dihydroxyvitamin D 3
39, method as claimed in claim 30, wherein said vitamin D compounds are 1 α, the 25-dihydroxyvitamin D 3
40, method as claimed in claim 30, wherein said vitamin D compounds are to be selected from any vitamin D analogies that can combine and activate the chemical compound of its transcriptional capability with VDR.
41, method as claimed in claim 30, wherein said bone calcium cell reabsorption inhibitor is selected from following group:
Estrogen,
Androgen,
Suppress the re-absorbed cytokine of bone,
The activator of peroxisome hypertrophy activated form receptor (PPAR) γ of thiazolidinediones,
Calcitonin,
Diphosphonate,
The receptor activators of NFkB (RANK) extracellular domain preparation,
The RANK analogies,
Solubility RANK-chimeric protein (RANK-Fc),
Protect ossein (OPG),
OPG chimeric protein (OPG-Fc),
The OPG analogies,
TNF receptor associated factor 6 (Traf6) is inveigled peptide,
Chimeric permeable membrane Traf6 inveigles peptide,
Traf6 inveigles peptide mimics,
The src inhibitor,
The outer receptor kinase (ERKs) of born of the same parents, the terminal kinases (JNKs) of c-Jun N-or inhibitor that stress activated protein kinase (SAPKs),
The micromolecular inhibitor of peptide/activator protein-I (AP-1),
The micromolecular inhibitor of peptide/c-Fos,
The micromolecular inhibitor of peptide/nuclear factor Kappa B (NFkB),
The micromolecular inhibitor of peptide/inhibition type kinase (IK) β,
The micromolecular inhibitor of peptide/inhibition type kinase (IK α, IK β, IKKs),
Film is in conjunction with the micromolecule antagonist of RANK,
The micromolecular inhibitor of RANK part trimerization or activation,
The inhibitor that contains RGD of the integrin that osteoclast is expressed,
The small molecule mimetics of integrin inhibitor,
Cathespin K inhibitor,
Tartrate tolerance acid phosphoric acid enzyme inhibitor, and
Vacuolate atpase inhibitor.
42, method as claimed in claim 30, wherein said bone calcium cell reabsorption inhibitor is an alendronate.
43, a kind of treatment is selected from the method for the autoimmune disease among multiple sclerosis, lupus, inflammatory bowel disease, type i diabetes, host-versus-graft reaction and the organ-graft refection, and it comprises with suitable dosage to the bone calcium cell reabsorption inhibitor of patient's effective dosage of suffering from above-mentioned disease and the vitamin D compounds of effective dose.
44, method as claimed in claim 43, the administration before vitamin D compounds of wherein said bone calcium cell reabsorption inhibitor.
45, method as claimed in claim 43, wherein said bone calcium cell reabsorption inhibitor basic and vitamin D compounds or analogies administration simultaneously.
46, method as claimed in claim 43, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are oral administrations.
47, method as claimed in claim 43, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are parenteral administrations.
48, method as claimed in claim 43, one of wherein said bone calcium cell reabsorption inhibitor and vitamin D compounds or both are transdermal administrations.
49, method as claimed in claim 43, wherein said vitamin D compounds are the dosed administrations with about 0.1 μ g/ days-100 μ g/ days, and described bone calcium cell reabsorption inhibitor is the dosed administration with about 7mg/ days-700mg/ days.
50, method as claimed in claim 43, wherein said vitamin D compounds is selected from the chemical compound with following structure
R wherein 6And R 7Represent hydrogen or R respectively 6And R 7A common methylene, the R of representing 8Represent hydrogen, hydroxyl or hydroxyl and protected, R 9And R 10Can distinguish and represent hydrogen, alkyl, hydroxy alkyl or fluoro-alkyl, perhaps R independently 9And R 10Can represent together x wherein for from 2 to 5 integer-(CH 2) X-group, group-OY or=R 11R 12, R wherein 11And R 12Can be identical or different, be selected from hydrogen, alkyl, hydroxy alkyl and fluoro-alkyl respectively, perhaps R 11And R 12Represent together x wherein for from 2 to 5 integer-(CH 2) X-group, and radicals R can be represented by the following formula structure
Figure A038248880015C2
Wherein the spatial chemistry center of 20 in carbon can be R or S configuration, and Z be selected from Y ,-OY ,-CH 2OY ,-C ≡ CY and-CH=CHY, wherein two keys can have cis or trans geometric isomer, and wherein Y be selected from hydrogen, methyl ,-COR 5The group following with structure:
Figure A038248880015C3
Wherein m and n represent 0 to 5 integer, wherein R independently 1Be selected from hydrogen, deuterium, hydroxyl, hydroxyl and protected, fluorine, trifluoromethyl and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, wherein R 2, R 3And R 4Be independently selected from deuterium, deuterium substituted alkyl, hydrogen, fluorine, trifluoromethyl respectively and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, and R wherein 1With R 2Common represent carbonyl or alkylidene ,=CR 2R 3, or wherein p be from 2 to 5 integers-(CH 2) P-group, wherein R 3With R 4Common represent carbonyl or wherein q be from 2 to 5 integers-(CH 2) q-group, wherein R 5Represent hydrogen, hydroxyl, hydroxyl and protected or C 1-5Alkyl, and wherein any CH group that is positioned at 20,22 or 23 of side chains can replace by nitrogen-atoms, perhaps wherein any be positioned at 20,22 and 23-CH (CH 3) ,-(CH 2) m,-(CR 1R 2)-or-(CH 2) n-can be replaced by oxygen or sulphur atom respectively.
51, method as claimed in claim 43, wherein said vitamin D compounds are 2-methylene-19-nor-20 (S)-1 α, the 25-dihydroxyvitamin D 3
52, method as claimed in claim 43, wherein said vitamin D compounds are 1 α, the 25-dihydroxyvitamin D 3
53, method as claimed in claim 43, wherein said vitamin D compounds are to be selected from any vitamin D analogies that can combine and activate the chemical compound of its transcriptional capability with VDR.
54, method as claimed in claim 43, wherein said bone calcium cell reabsorption inhibitor is selected from following group:
Estrogen,
Androgen,
Suppress the re-absorbed cytokine of bone,
The activator of peroxisome hypertrophy activated form receptor (PPAR) γ of thiazolidinediones,
Calcitonin,
Diphosphonate,
The receptor activators of NFkB (RANK) extracellular domain preparation,
The RANK analogies,
Solubility RANK-chimeric protein (RANK-Fc),
Protect ossein (OPG),
OPG chimeric protein (OPG-Fc),
The OPG analogies,
TNF receptor associated factor 6 (Traf6) is inveigled peptide,
Chimeric permeable membrane Traf6 inveigles peptide,
Traf6 inveigles peptide mimics,
The src inhibitor,
The outer receptor kinase (ERKs) of born of the same parents, the terminal kinases (JNKs) of c-Jun N-or inhibitor that stress activated protein kinase (SAPKs),
The micromolecular inhibitor of peptide/activator protein-I (AP-1),
The micromolecular inhibitor of peptide/c-Fos,
The micromolecular inhibitor of peptide/nuclear factor Kappa B (NFkB),
The micromolecular inhibitor of peptide/inhibition type kinase (IK) β,
The micromolecular inhibitor of peptide/inhibition type kinase (IK α, IK β, IKKs),
Film is in conjunction with the micromolecule antagonist of RANK,
The micromolecular inhibitor of RANK part trimerization or activation,
The inhibitor that contains RGD of the integrin that osteoclast is expressed,
The small molecule mimetics of integrin inhibitor,
Cathespin K inhibitor,
Tartrate tolerance acid phosphoric acid enzyme inhibitor, and
Vacuolate atpase inhibitor.
55, method as claimed in claim 43, wherein said bone calcium cell reabsorption inhibitor is an alendronate.
56, a kind of pharmaceutical composition that comprises vitamin D compounds and bone calcium cell reabsorption inhibitor and the acceptable excipient of materia medica.
57, pharmaceutical composition as claimed in claim 56, it comprises the vitamin D compounds of the about 0.1 μ g-100 μ g of every gram compositions.
58, pharmaceutical composition as claimed in claim 56, wherein said vitamin D compounds is selected from the chemical compound with following structure
R wherein 6And R 7Represent hydrogen or R respectively 6And R 7A common methylene, the R of representing 8Represent hydrogen, hydroxyl or hydroxyl and protected, R 9And R 10Can distinguish and represent hydrogen, alkyl, hydroxy alkyl or fluoro-alkyl, perhaps R independently 9And R 10Can represent together x wherein for from 2 to 5 integer-(CH 2) X-group, group-OY or=R 11R 12, R wherein 11And R 12Can be identical or different, be selected from hydrogen, alkyl, hydroxy alkyl and fluoro-alkyl respectively, perhaps R 11And R 12Represent together x wherein for from 2 to 5 integer-(CH 2) X-group, and radicals R can be represented by the following formula structure
Wherein the spatial chemistry center of 20 in carbon can be R or S configuration, and Z be selected from Y ,-OY ,-CH 2OY ,-C ≡ CY and-CH=CHY, wherein two keys can have cis or trans geometric isomer, and wherein Y be selected from hydrogen, methyl ,-COR 5The group following with structure:
Wherein m and n represent 0 to 5 integer, wherein R independently 1Be selected from hydrogen, deuterium, hydroxyl, hydroxyl and protected, fluorine, trifluoromethyl and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, wherein R 2, R 3And R 4Be independently selected from deuterium, deuterium substituted alkyl, hydrogen, fluorine, trifluoromethyl respectively and can be straight or branched and can randomly have hydroxyl or the substituent C of hydroxyl and protected 1-5Alkyl, and R wherein 1With R 2Common represent carbonyl or alkylidene ,=CR 2R 3, or wherein p be from 2 to 5 integers-(CH 2) P-group, wherein R 3With R 4Common represent carbonyl or wherein q be from 2 to 5 integers-(CH 2) q-group, wherein R 5Represent hydrogen, hydroxyl, hydroxyl and protected or C 1-5Alkyl, and wherein any CH group that is positioned at 20,22 or 23 of side chains can replace by nitrogen-atoms, perhaps wherein any be positioned at 20,22 and 23-CH (CH 3) ,-(CH 2) m,-(CR 1R 2)-or-(CH 2) n-can be replaced by oxygen or sulphur atom respectively.
59, pharmaceutical composition as claimed in claim 56, wherein said vitamin D compounds are 2-methylene-19-nor-20 (S)-1 α, the 25-dihydroxyvitamin D 3
60, pharmaceutical composition as claimed in claim 56, wherein said vitamin D compounds are 1 α, the 25-dihydroxyvitamin D 3
61, pharmaceutical composition as claimed in claim 56, wherein said vitamin D compounds are to be selected from any vitamin D analogies that can combine and activate the chemical compound of its transcriptional capability with VDR.
62, pharmaceutical composition as claimed in claim 56, it comprises the bone calcium cell reabsorption inhibitor of the about 7mg-700mg of every gram compositions.
63, pharmaceutical composition as claimed in claim 56, wherein said bone calcium cell reabsorption inhibitor is selected from following group:
Estrogen,
Androgen,
Suppress the re-absorbed cytokine of bone,
The activator of peroxisome hypertrophy activated form receptor (PPAR) γ of thiazolidinediones,
Calcitonin,
Diphosphonate,
The receptor activators of NFkB (RANK) extracellular domain preparation,
The RANK analogies,
Solubility RANK-chimeric protein (RANK-Fc),
Protect ossein (OPG),
OPG chimeric protein (OPG-Fc),
The OPG analogies,
TNF receptor associated factor 6 (Traf6) is inveigled peptide,
Chimeric permeable membrane Traf6 inveigles peptide,
Traf6 inveigles peptide mimics,
The src inhibitor,
The outer receptor kinase (ERKs) of born of the same parents, the terminal kinases (JNKs) of c-Jun N-or inhibitor that stress activated protein kinase (SAPKs),
The micromolecular inhibitor of peptide/activator protein-I (AP-1),
The micromolecular inhibitor of peptide/c-Fos,
The micromolecular inhibitor of peptide/nuclear factor Kappa B (NFkB),
The micromolecular inhibitor of peptide/inhibition type kinase (IK) β,
The micromolecular inhibitor of peptide/inhibition type kinase (IK α, IK β, IKKs),
Film is in conjunction with the micromolecule antagonist of RANK,
The micromolecular inhibitor of RANK part trimerization or activation,
The inhibitor that contains RGD of the integrin that osteoclast is expressed,
The small molecule mimetics of integrin inhibitor,
Cathespin K inhibitor,
Tartrate tolerance acid phosphoric acid enzyme inhibitor, and
Vacuolate atpase inhibitor.
64, pharmaceutical composition as claimed in claim 56, wherein said bone calcium cell reabsorption inhibitor is an alendronate.
65, pharmaceutical composition as claimed in claim 56, it is used for oral administration by preparation.
66, pharmaceutical composition as claimed in claim 56, it is used for parenteral administration by preparation.
67, pharmaceutical composition as claimed in claim 56, it is used for transdermal administration by preparation.
68, pharmaceutical composition as claimed in claim 56, it is used for topical by preparation.
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Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030188756A1 (en) * 2002-08-19 2003-10-09 Cantorna Margherita T Treatment of inflammatory bowel disease with vitamin d compounds
WO2003086415A1 (en) * 2002-04-05 2003-10-23 Merck & Co., Inc. Method for inhibiting bone resorption with an alendronate and vitamin d formulation
US20080249068A1 (en) * 2002-09-05 2008-10-09 Deluca Hector F Method of Extending the Dose Range of Vitamin D Compounds
US7566696B2 (en) * 2002-09-05 2009-07-28 Wisconsin Alumni Research Foundation Use of calcitonin and calcitonin-like peptides to treat and prevent multiple sclerosis
WO2005018658A1 (en) * 2003-08-20 2005-03-03 Wisconsin Alumni Research Foundation 2-methylene-19-nor-vitamin d2 compounds
EP1667692A1 (en) * 2003-09-19 2006-06-14 Pfizer Products Inc. Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and an estrogen agonist/antagonist
WO2005027929A1 (en) * 2003-09-19 2005-03-31 Pfizer Products Inc. Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and an estrogen
US7704980B2 (en) * 2003-10-08 2010-04-27 Wisconsin Alumni Research Foundation Treatment of inflammatory bowel disease with 2-methylene-19-nor-vitamin D compounds
US20050261250A1 (en) * 2004-05-19 2005-11-24 Merck & Co., Inc., Compositions and methods for inhibiting bone resorption
WO2006061683A1 (en) * 2004-12-09 2006-06-15 Pfizer Products Inc. 2-alkylidene-19-nor-vitamin d derivatives for the treatment of osteogenesis imperfecta
WO2006086661A2 (en) * 2005-02-10 2006-08-17 Above Sea Level, Llc Lead generation method and system
US7511030B2 (en) * 2005-02-11 2009-03-31 Wisconsin Alumni Research Foundation 2-methylene-19-nor-(20S-24epi)-1α,25-dihydroxyvitamin D2
CA2597624C (en) * 2005-02-11 2012-08-14 Wisconsin Alumni Research Foundation 2-methylene-19-nor-(20s-24s)-1.alpha.,25-dihydroxyvitamin-d2
WO2006088765A1 (en) * 2005-02-14 2006-08-24 Wisconsin Alumni Research Foundation Use of calcitonin and calcitonin-like peptides to treat and prevent multiple sclerosis
CN101287705A (en) * 2005-08-18 2008-10-15 拜奥艾克塞尔股份公司 Synthesis of 1alpha-fluoro-25-hydroxy-16-23e-diene-26,27-bishomo-20-epi-cholecalciferol
US20070165866A1 (en) * 2006-01-13 2007-07-19 Motorola, Inc. Method and apparatus to facilitate conveying audio content
DK2481400T3 (en) * 2007-04-25 2014-09-29 Opko Ip Holdings Ii Inc Controlled-release oral preparations comprising a vitamin D compound and a waxy carrier
US20100331286A1 (en) * 2008-02-25 2010-12-30 Ray Chow Combination therapy for treatment of bone and mineral disorders for patients with impaired renal function
TR200900880A2 (en) 2009-02-05 2010-08-23 Bi̇lgi̇ç Mahmut Pharmaceutical compositions combined in a single dosage form.
TR200900878A2 (en) 2009-02-05 2010-08-23 Bi̇lgi̇ç Mahmut Pharmaceutical formulations combined in a single dosage form
AU2010300539B9 (en) * 2009-10-02 2018-07-19 Wisconsin Alumni Research Foundation 1-desoxy-2-methylene-19-nor-vitamin D analogs and their uses
WO2012075326A2 (en) * 2010-12-01 2012-06-07 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Treatment of inflammatory diseases by targeting the adaptor protein ciks
JP6114292B2 (en) * 2011-10-21 2017-04-12 ウイスコンシン アラムニ リサーチ ファンデーション 2-Methylene-vitamin D analogs and their use
CA2991260A1 (en) * 2015-08-05 2017-02-09 Wisconsin Alumni Research Foundation Synthesis and biological activity of 2-methylene analogs of calcitriol and related compounds

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6357527A (en) 1986-08-28 1988-03-12 Toyo Jozo Co Ltd Method for preventing adsorption of drug
US5391567A (en) * 1986-09-03 1995-02-21 Macrochem Corporation Method for treating hypercalcemia using salts of TNCA
US6489288B1 (en) * 1990-03-16 2002-12-03 Applied Research Systems Ars Holding Treatment of polycystic ovarian disease
US5780437A (en) * 1995-12-14 1998-07-14 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
US6613544B1 (en) 1995-12-22 2003-09-02 Amgen Inc. Osteoprotegerin
US6369027B1 (en) 1995-12-22 2002-04-09 Amgen Inc. Osteoprotegerin
US6271349B1 (en) 1996-12-23 2001-08-07 Immunex Corporation Receptor activator of NF-κB
US6503893B2 (en) * 1996-12-30 2003-01-07 Bone Care International, Inc. Method of treating hyperproliferative diseases using active vitamin D analogues
US5843928A (en) * 1997-03-17 1998-12-01 Wisconsin Alumni Research Foundation 2-alkylidene-19-nor-vitamin D compounds
US6034075A (en) * 1997-03-20 2000-03-07 The Trustees Of Columbia University In The City Of New York Method of treating polycystic ovarian syndrome
US6316408B1 (en) 1997-04-16 2001-11-13 Amgen Inc. Methods of use for osetoprotegerin binding protein receptors
US5843678A (en) 1997-04-16 1998-12-01 Amgen Inc. Osteoprotegerin binding proteins
US6087555A (en) 1997-10-15 2000-07-11 Amgen Inc. Mice lacking expression of osteoprotegerin
AU3316600A (en) 1999-02-22 2000-09-21 Torben F. Orntoft Gene expression in bladder tumors
AU2756701A (en) 2000-01-04 2001-07-16 Regents Of The University Of California, The Use of low dosage bisphosphonates to inhibit cardiac and arterial calcification
CA2454200A1 (en) * 2001-07-17 2003-01-30 Teva Pharmaceutical Industries Ltd. Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate

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